The induction of peripheral tolerance is critical for deterrence of autoimmunity. As a gateway to the external environment the intestinal mucosal immune system faces a unique set of challenges in controlling ongoing protective innate and adaptive immune responses, while maintaining tissue integrity. The tissue dynamics of the intestine, including rapid cellular turnover and absorption of nutrients, also require specialized management systems. Although many experimental models have been employed to understand the control of autoimmunity in the intestinal mucosa, much remains to be learned regarding the induction of tolerance to tissue-specific and developmentally regulated antigens. We have developed a system in which the expression of neo-self-antigens in intestinal epithelial cells can be temporally controlled. The system provides the ability to inducibly regulate antigen expression and tolerance induction in the intestinal mucosa. The aims of the proposal are: Aim 1. To determine the parameters of IEC antigen acquisition and presentation in the intestinal mucosa. Aim 2. To determine the requirements for induction of T cell tolerance to developmentally regulated intestine-specific antigen. Aim 3. To determine the consequences of memory T cell encounter with developmentally regulated antigen. The proposed studies will help define the mechanisms controlling tolerance versus autoimmunity in the intestinal mucosa. [unreadable] [unreadable]